Significance The impact of inhaled particulates is a growing health concern worldwide. The mechanisms leading to increased morbidity and mortality among individuals exposed to particulate matter are unknown. Objectives The goal of this proposal is to examine the mechanisms of particulate toxicity in the lungs of monkeys following short (1-3 day) and long-term (28 day) exposure to particles that directly impact on epithelial cells of the airways, respiratory bronchioles, and alveoli. Since epithelial cells are the first cells in the respiratory tract to come into contact with inhaled particles, we hypothesize that damage to these cells can serve as a direct and highly sensitive measure of particle toxicity. We hypothesize that epithelial cells lining the transitional zone between the airways and gas exchange regions of the lungs (i.e., the respiratory bronchiole) are particularly sensitive and play a key role in the initiation and progression of particle-induced pulmonary injury. We will test these hypotheses using novel approaches to examine epithelial cell structure and function throughout the airways and alveoli. Expected Results Those mechanisms by which particles may exert an adverse effect(s) on the cardiopulmonary system should be identified to better define the current human epidemiologic data on PM10 effects. The importance of the respiratory bronchiole in particle deposition, translocation, and retention/clearance and associated particle-induced lung injury will be directly examined in two animal models (i.e. rat and monkey) to better extrapolate our findings to humans. Future Directions This work has just recently received approval for funding from the Environmental Protection Agency. We plan to use state-of-the-art techniques to measure epithelial cytotoxicity, proliferation, antioxidant capacity and epithelial particle clearance will be used. The effects of co-exposure of particles with ozone will also be examined to determine the potential for interactive effects in what should constitute a better simulation of "real-world" exposure conditions.